The role of interferon signaling in neurodegeneration and neuropsychiatric disorders

Daniel W Sirkis; Alexis P Oddi; Caroline Jonson; Luke W Bonham; Phuong T Hoang; Jennifer S Yokoyama

doi:10.3389/fpsyt.2024.1480438

The role of interferon signaling in neurodegeneration and neuropsychiatric disorders

Front Psychiatry. 2024 Oct 3:15:1480438. doi: 10.3389/fpsyt.2024.1480438. eCollection 2024.

Authors

Daniel W Sirkis¹, Alexis P Oddi¹, Caroline Jonson^{1

2

3}, Luke W Bonham^{1

4}, Phuong T Hoang⁵, Jennifer S Yokoyama^{1

4

6}

Affiliations

¹ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States.
² Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, United States.
³ DataTecnica LLC, Washington, DC, United States.
⁴ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States.
⁵ Movement Disorders and Neuromodulation Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States.
⁶ Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, United States.

Abstract

Recent advances in transcriptomics research have uncovered heightened interferon (IFN) responses in neurodegenerative diseases including Alzheimer's disease, primary tauopathy, Parkinson's disease, TDP-43 proteinopathy, and related mouse models. Augmented IFN signaling is now relatively well established for microglia in these contexts, but emerging work has highlighted a novel role for IFN-responsive T cells in the brain and peripheral blood in some types of neurodegeneration. These findings complement a body of literature implicating dysregulated IFN signaling in neuropsychiatric disorders including major depression and post-traumatic stress disorder. In this review, we will characterize and integrate advances in our understanding of IFN responses in neurodegenerative and neuropsychiatric disease, discuss how sex and ancestry modulate the IFN response, and examine potential mechanistic explanations for the upregulation of antiviral-like IFN signaling pathways in these seemingly non-viral neurological and psychiatric disorders.

Keywords: Alzheimer’s disease; C9orf72; Parkinson’s disease; TDP-43; autoimmune disease; interferon; neurodegeneration; neuropsychiatric disease.

Publication types

Review

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. JY receives funding from NIH-NIA R01AG062588, R01AG057234, P30AG062422, P01AG019724, and U19AG079774; NIH-NINDS U54NS123985; NIH-NIDA 75N95022C00031; the Rainwater Charitable Foundation; the Bluefield Project to Cure Frontotemporal Dementia; the Alzheimer’s Association; the Global Brain Health Institute; the French Foundation; and the Mary Oakley Foundation. CJ’s participation in this project was part of a competitive contract awarded to DataTecnica by the National Institutes of Health (NIH) to support open science research. CJ was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA); project number ZO1 AG000534, as well as the National Institute of Neurological Disorders and Stroke (NINDS). LB receives funding from NIH-NIBIB T32 EB001631 and RSNA R&E Foundation RR24–217. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the RSNA R&E Foundation.